Dodd 2018

Cochrane Database of Systematic Reviews
Metformin for women who are overweight or obese during

pregnancy for improving maternal and infant outcomes
(Review)
Dodd JM, Grivell RM, Deussen AR, Hague WM
Dodd JM, Grivell RM, Deussen AR, Hague WM.

Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes.
Cochrane Database of Systematic Reviews 2018, Issue 7. Art. No.: CD010564.
DOI: 10.1002/14651858.CD010564.pub2.
www.cochranelibrary.com
Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes (Review)
Copyright © 2018 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
Analysis 1.1. Comparison 1 Metformin versus placebo, Outcome 1 Large-for-gestational-age infant, defined as birthweight
≥ 90th percentile for gestational age and infant sex. . . . . . . . . . . . . . . . . . . . . . 30
Analysis 1.2. Comparison 1 Metformin versus placebo, Outcome 2 Gestational weight gain (kg). . . . . . . . 30
Analysis 1.3. Comparison 1 Metformin versus placebo, Outcome 3 Gestational hypertension. . . . . . . . . 31
Analysis 1.4. Comparison 1 Metformin versus placebo, Outcome 4 Pre-eclampsia. . . . . . . . . . . . . 32
Analysis 1.5. Comparison 1 Metformin versus placebo, Outcome 5 Gestational diabetes. . . . . . . . . . . 32
Analysis 1.6. Comparison 1 Metformin versus placebo, Outcome 6 Preterm birth (before 37 weeks). . . . . . . 33
Analysis 1.7. Comparison 1 Metformin versus placebo, Outcome 7 Preterm premature rupture of membranes. . . 34
Analysis 1.8. Comparison 1 Metformin versus placebo, Outcome 8 Induction of labour. . . . . . . . . . . 34
Analysis 1.9. Comparison 1 Metformin versus placebo, Outcome 9 Vaginal birth. . . . . . . . . . . . . 35
Analysis 1.10. Comparison 1 Metformin versus placebo, Outcome 10 Caesarean birth. . . . . . . . . . . . 35
Analysis 1.11. Comparison 1 Metformin versus placebo, Outcome 11 Shoulder dystocia. . . . . . . . . . . 36
Analysis 1.12. Comparison 1 Metformin versus placebo, Outcome 12 Third- or fourth-degree perineal tear. . . . 36
Analysis 1.13. Comparison 1 Metformin versus placebo, Outcome 13 Adverse effects of the treatment: at least one. . 37
Analysis 1.14. Comparison 1 Metformin versus placebo, Outcome 14 Adverse effects of the treatment: abdominal pain. 37
Analysis 1.15. Comparison 1 Metformin versus placebo, Outcome 15 Adverse effects of the treatment: diarrhoea. . 38
Analysis 1.16. Comparison 1 Metformin versus placebo, Outcome 16 Adverse effects of the treatment: headache. . 38
Analysis 1.17. Comparison 1 Metformin versus placebo, Outcome 17 Postpartum haemorrhage. . . . . . . . 39
Analysis 1.18. Comparison 1 Metformin versus placebo, Outcome 18 Birthweight (g). . . . . . . . . . . . 40
Analysis 1.19. Comparison 1 Metformin versus placebo, Outcome 19 Hypoglycaemia requiring treatment. . . . . 40
Analysis 1.20. Comparison 1 Metformin versus placebo, Outcome 20 Hyperbilirubinaemia requiring treatment. . . 41
Analysis 1.21. Comparison 1 Metformin versus placebo, Outcome 21 Birth trauma. . . . . . . . . . . . . 41
Analysis 1.22. Comparison 1 Metformin versus placebo, Outcome 22 Apgar less than 7 at five minutes. . . . . . 42
Analysis 1.23. Comparison 1 Metformin versus placebo, Outcome 23 NICU/Neonatal unit admission. . . . . . 42
Analysis 1.24. Comparison 1 Metformin versus placebo, Outcome 24 Stillbirth. . . . . . . . . . . . . . 43
Analysis 1.25. Comparison 1 Metformin versus placebo, Outcome 25 Neonatal death. . . . . . . . . . . . 43
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 45
Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes (Review) i
[Intervention Review]
Metformin for women who are overweight or obese during

pregnancy for improving maternal and infant outcomes
Jodie M Dodd1 , Rosalie M Grivell2 , Andrea R Deussen1 , William M Hague3

1
School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The University of Adelaide, Women’s and
Children’s Hospital, Adelaide, Australia. 2 Department of Obstetrics and Gynaecology, Flinders University and Flinders Medical Centre,
Bedford Park, Australia. 3 Women’s and Children’s Hospital, Adelaide, Australia
Contact address: Jodie M Dodd, School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, The
University of Adelaide, Women’s and Children’s Hospital, 72 King William Road, Adelaide, South Australia, 5006, Australia.
jodie.dodd@adelaide.edu.au.
Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 7, 2018.
Citation: Dodd JM, Grivell RM, Deussen AR, Hague WM. Metformin for women who are overweight or obese during pregnancy
for improving maternal and infant outcomes. Cochrane Database of Systematic Reviews 2018, Issue 7. Art. No.: CD010564. DOI:
10.1002/14651858.CD010564.pub2.
ABSTRACT
Background
There has been considerable interest in providing antenatal dietary and lifestyle advice for women with obesity or who are overweight
during pregnancy, as a strategy to limit gestational weight gain and improve maternal and infant health. However, such antenatal
interventions appear to have a modest effect on gestational weight gain and other clinical pregnancy and birth outcomes and additional
strategies are required.
Metformin is an oral insulin-sensitising medication that acts to decrease blood glucose concentrations. Metformin is commonly used in
the treatment of type 2 diabetes mellitus and polycystic ovarian syndrome, and is being used increasingly in the treatment of gestational
diabetes, having been shown to result in decreased rates of caesarean birth and neonatal hypoglycaemia. Metformin may be an adjuvant
therapy to current antenatal strategies in pregnant women with obesity or who are overweight, acting to reduce glucose production in
the liver and improve glucose uptake in smooth muscle cells, and therefore improve the overall metabolic health of women in pregnancy
and reduce the risk of known adverse pregnancy outcomes.
Objectives
To evaluate the role of metformin in pregnant women with obesity or who are overweight, on maternal and infant outcomes, including
adverse effects of treatment and costs.
Search methods
We searched Cochrane Pregnancy and Childbirth’s Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) Inter-
national Clinical Trials Registry Platform ( ICTRP) (11 October 2017), and reference lists of retrieved studies.
Selection criteria
All published and unpublished randomised controlled trials evaluating metformin use (compared with placebo or no metformin) in
women with obesity or who are overweight in pregnancy for improving outcomes, alone or in combination with other interventions
were eligible for inclusion.
Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes (Review) 1
Data collection and analysis
Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We used
the GRADE approach to assess the quality of the evidence.
Main results
We included three studies which randomised women (1099) with a body mass index (BMI) of 30 kg/m2 (1 study) and 35 kg/m2 (2
studies), with outcomes available for 1034 participants. None of the studies assessed women with a BMI between 25 kg/m2 and 29.9
kg/m2 , therefore we could not assess the use of metformin in women considered overweight. We did not identify studies of metformin
in combination with another treatment. Two other studies are ongoing.
All three included studies were randomised controlled trials and compared metformin with placebo, commencing early in the second
trimester. Doses ranged from 500 mg twice daily to 3.0 g per day. All three studies (two in the UK, one in Egypt) included women
attending hospitals for antenatal care.
Two studies were generally at a low risk of bias across the majority of domains. We assessed the third study as being at an unclear risk
of selection bias, performance and detection bias due to insufficient information in the report. We assessed the trial as being at a low
risk of attrition bias and other bias; we felt it was at a high risk of reporting bias.
The primary outcome for this review was infant birthweight large-for-gestational-age (> 90th centile for gestational age and infant sex).
Women who received metformin or placebo had a similar risk of their baby being born large for his or her gestational age (risk ratio
(RR) 0.95, 95% confidence interval (CI) 0.70 to 1.30; 2 studies, 831 infants; high-quality evidence).
Women who received metformin may have a slightly lower gestational weight gain (mean difference (MD) -2.60 kg, 95% CI -5.29 to
0.10; 3 studies, 899 women; low-quality evidence).
Metformin may make little or no difference in the risk of women developing gestational hypertension (average RR 1.02, 95% CI 0.54
to 1.94; 3 studies, 1040 women; low-quality evidence) or pre-eclampsia (RR 0.74, 95% CI 0.09 to 6.28; 2 studies, 840 women; low-
quality evidence). Metformin probably makes little or no difference in the risk of women developing gestational diabetes (RR 0.85,
95% CI 0.61 to 1.19; 3 studies, 892 women; moderate-quality evidence).
One study of 400 women reported women receiving metformin were more likely to experience any adverse effect compared with
women receiving placebo (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women). Adverse effects included abdominal pain, diarrhoea, or
headache. When considering individual side effects, women receiving metformin were more likely to experience diarrhoea than women
receiving placebo (RR 2.34, 95% CI 1.74 to 3.14; 797 women; 2 studies, 797 women; high-quality evidence). No other important
differences were identified between Metformin and placebo for other maternal secondary outcomes, including: caesarean birth, birth
before 37 weeks of pregnancy, shoulder dystocia, perineal tear, or postpartum haemorrhage.
In terms of other infant outcomes, there was little or no difference in the infant birthweight (MD 6.39 g, 95% CI -81.15 to 93.92; 2
studies, 834 infants; high-quality evidence). There were no other important differences identified for other infant secondary outcomes
in this review: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice); Apgar score less than 7 at five minutes; or stillbirth and
neonatal death. Only one study reported admission to the neonatal intensive care unit (NICU), indicating similar rates of admission
between women receiving metformin or placebo; no other admission data were reported to assess differences in costs.
Authors’ conclusions
There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving maternal and infant
outcomes. Metformin was, however, associated with increased risk of adverse effects, particularly diarrhoea. The quality of the evidence
in this review varied from high to low, with downgrading decisions based on study limitations and inconsistency.
There were only a small number of studies included in this review. Furthermore, none of the included studies included women
categorised as ’overweight’ and no trials looked at metformin in combination with another treatment.
Future research is required in order to further evaluate the role of metformin therapy in pregnant women with obesity or who are
overweight, as a strategy to improve maternal and infant health, alone or as an adjuvant to dietary and lifestyle advice.
PLAIN LANGUAGE SUMMARY

Metformin for women with obesity or who are overweight during pregnancy for improving health for women and their babies
What is the issue?
We examined whether metformin has a role in improving health outcomes for pregnant women with obesity or who are overweight,
and their babies. We considered possible benefits, adverse effects and healthcare system costs.
Body mass index (BMI), calculated from a person’s height and weight, is used to classify someone as having normal weight (BMI less
than 25 kg/m2 ), being overweight (BMI 24.9 kg/m2 to 30 kg/m2 ) or having obesity (BMI above 30 kg/m2 ). Women with obesity or
who are overweight are more likely than women of normal weight to experience complications like high blood pressure and gestational
diabetes during pregnancy. They are also at increased risk of needing a caesarean or developing infection after birth. Their babies are
more likely to experience health problems, requiring admission to the neonatal unit or intensive care, have low blood sugar, or problems
breathing immediately after birth.
Women with obesity or who are overweight may have some features of diabetes that may contribute to problems during pregnancy and
birth. They may not process dietary carbohydrates and sugars efficiently, and are more likely to be resistant to the hormone insulin,
released by the pancreas after eating, helping muscles use blood glucose (sugar) for energy. Glucose circulates in the blood for longer,
providing excess energy to the growing baby. There is an increased risk of developing diabetes in pregnancy and women may have low
levels of inflammatory hormones and proteins circulating in the body. Improving diet and increasing exercise have had a very small
effect on reducing weight gain during pregnancy and no effect on complications.
Metformin, a drug used to treat diabetes, reduces the amount of glucose the liver releases into the blood and makes the body more
sensitive to insulin. Metformin may help a woman’s body use insulin more effectively and reduce the chance that her baby will grow
large-for-gestational age.
What evidence did we find?
We searched for evidence (October 2017) and found three randomised controlled studies (1099 pregnant women) comparing metformin
tablets with placebo (dummy) tablets taken by mouth from 10 to 20 weeks of pregnancy until birth. The studies involved women with
obesity; we therefore could not assess the effect of metformin in women who are overweight.
Women who were given metformin or placebo during pregnancy had a similar risk of a baby being born large-for-gestational age
(measured in weeks since last period). Metformin probably makes little or no difference in the risk of women developing gestational
diabetes. Metformin may also have little or no difference in the risk of women developing gestational hypertension (high blood pressure)
or pre-eclampsia.
Women who were given metformin may gain slightly less weight during pregnancy, but are more likely to experience diarrhoea. There
were no other important differences identified for other maternal outcomes including, caesarean birth, giving birth before 37 weeks of
pregnancy, shoulder dystocia (a birth complication where the baby’s shoulder gets stuck), perineal trauma (damage to the area between
the woman’s vagina and the anus), or heavy bleeding after the baby has been born.
Babies of women who were given metformin had similar birthweight to babies of women who were given placebo. We did not identify
any other important differences for other infant outcomes of interest: hypoglycaemia (low blood sugar); hyperbilirubinaemia (jaundice);
Apgar score at five minutes (a measure of newborn well-being); or death of the baby before or after being born. One study reported
similar rates of admission to neonatal intensive care between groups.
What does this mean?
There is insufficient evidence to support the use of metformin for women with obesity in pregnancy for improving outcomes for the
mother and her baby. Metform was associated with increased risk of adverse effects, particularly diarrhoea.
A small number of studies are included in this review and no study included women categorised as ’overweight’, or looked at metformin
in combination with another treatment.
More research is needed to evaluate the role of metformin in pregnant women with obesity or who are overweight, as a strategy for
improving maternal and infant health, either alone or as an additional intervention.
Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
M etformin compared to placebo for women with obesity during pregnancy
Patient or population: wom en with obesity during pregnancy

Setting: antenatal clinics in the UK (2 trials) and Egypt (1 trial)
Intervention: m etf orm in tablets taken orally
Comparison: placebo
Outcomes Anticipated absolute effects∗ (95% CI) Relative effect of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Risk with placebo Risk with metformin
Large- for- Study population RR 0.95 831 ⊕⊕⊕⊕

gestational- age infant, (0.70 to 1.30) (2 RCTs) HIGH
defined as birthweight
≥ 90th percentile for
gestational age and in- 164 per 1000 156 per 1000
fant sex (115 to 213)
Gestational weight The m ean gestational M D 2.60 kilogram s - 899 ⊕⊕

gain (kg) weight gain across con- lower (3 RCTs) LOW a,b
trol groups ranged f rom (5.29 lower to 0.10
6.4 kg to 11.61 kg higher)
Gestational hyperten- Study population Average RR 1.02 1040 ⊕⊕

sion (0.54 to 1.94) (3 RCTs) LOW a,b
64 per 1000 65 per 1000
(34 to 124)
Pre- eclampsia Study population Average RR 0.74 840 ⊕⊕

(0.09 to 6.28) (2 RCTs) LOW b,c
60 per 1000 44 per 1000
(5 to 376)
4
Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes (Review)
Gestational diabetes Study population RR 0.85 892 ⊕⊕⊕

(as defined by the trial (0.61 to 1.19) (3 RCTs) M ODERATE a
authors) 143 per 1000 121 per 1000
(87 to 170)
Adverse effects asso- Study population RR 2.34 797 ⊕⊕⊕⊕

ciated with the treat- (1.74 to 3.14) (2 RCTs) HIGH
ment: diarrhoea 126 per 1000 295 per 1000
(220 to 396)
Birthweight (g) The m ean birthweight M D 6.39 gram s higher - 834 ⊕⊕⊕⊕
across control groups (81.15 lower to 93.92 (2 RCTs) HIGH
ranged f rom 3341 g to higher)
3463 g
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; M D: m ean dif f erence; RCT: random ised controlled trial; RR: risk ratio.
GRADE Working Group grades of evidence

High quality: we are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect
M oderate quality: we are m oderately conf ident in the ef f ect estim ate: the true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent
Low quality: our conf idence in the ef f ect estim ate is lim ited: the true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect
Very low quality: we have very little conf idence in the ef f ect estim ate: the true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
a Downgraded (-1) f or study lim itations. One study of the three studies included has unclear risk of bias f or random sequence
generation, allocation concealm ent, perf orm ance bias, outcom e assessor bias and selective reporting bias and reports a
m uch greater ef f ect than the other two studies.
b Substantial heterogeneity - downgraded f or inconsistency (-1).
c
Downgraded (-1) f or im precision - wide conf idence intervals crossing the line of no ef f ect.
5
BACKGROUND Description of the intervention
Metformin is an oral insulin-sensitising medication that acts to
decrease blood glucose concentrations. It inhibits pathways in the
liver that stimulate glucose production and also acts to increase
Description of the condition glucose uptake into skeletal muscle and fat cells (Bailey 1996; Cusi
Obesity and being overweight affects more than 1.9 billion adults 1998; Hundal 2000; Inzucchi 1998; Large 1999; Perriello 1994;
(WHO 2017), 41 million children under the age of five years Wiernsperger 1999). Metformin is commonly used in the treat-
(WHO 2013), and 270 million children aged five to 17 years ment of type 2 diabetes mellitus and polycystic ovarian syndrome
(Lobstein 2016), across the globe. ’Overweight’ is defined as an (Levri 2005), and is being used increasingly in the treatment of
individual with body mass index (BMI) between 25.0 kg/m2 and gestational diabetes, having been shown to result in decreased
29.9 kg/m2 , while obesity is defined as a BMI above 30.0 kg/m2 rates of neonatal hypoglycaemia and no increased risk of adverse
(WHO 2000). Obesity and being overweight represents a signifi- maternal outcomes when compared with insulin (Priya 2018). A
cant disease burden, contributing to hypertension, cardiovascular Cochrane Review aimed to evaluate antenatal interventions for
disease and diabetes, and their complications (Ezzati 2002). Fur- reducing weight in women with obesity for improving outcomes,
thermore, obesity and being overweight have been estimated to however, no randomised controlled trials were identified (Furber
contribute to more than 5% of deaths globally each year (WHO 2013).
2009).
Obesity and being overweight are associated with significant eco-
nomic implications, both for the individual and society (Wang
How the intervention might work
2011), accounting for 36 million disability-adjusted life years
(DALYs). Medical costs for individuals with obesity are esti- Metformin may be an adjuvant therapy to current antenatal strate-
mated to be 30% higher than for individuals with a normal BMI gies in pregnant women with obesity or who are overweight, act-
(Withrow 2009), and contribute to increasing health and medical ing to reduce glucose production in the liver and improve glu-
expenditure at a population level (Thompson 2001; Wang 2008). cose uptake in smooth muscle cells, and therefore improve the
Obesity and being overweight in pregnancy affects approximately overall metabolic health of women in pregnancy. Metformin also
50% of women across low-income nations (Chu 2009; Ng 2013; has weight loss effects, attributed to decreased net caloric intake,
Scheil 2015); and is associated with a range of well recognised ma- most likely through appetite suppression (Kirpichnikov 2002).
ternal and infant health complications. Maternal risks include ges- Importantly, adverse effects related to metformin are uncommon,
tational hypertension, pre-eclampsia (disorders of blood pressure with no reported associations with birth defects (Gilbert 2006;
in pregnancy), and gestational diabetes; women are more likely Hawthorne 2006; Lilja 2006), and being increasingly used to treat
to have their labour induced, and to birth by caesarean section gestational diabetes (Balsells 2015).
(Callaway 2006; Dodd 2011). Infants born to women with obe-
sity or who are overweight in pregnancy have a higher risk of be-
ing of high birthweight or being large-for-gestational age, and of
associated complications, including shoulder dystocia (difficulty
Why it is important to do this review
in the delivery of the infant’s shoulders), admission to neonatal The role of metformin in pregnancy for women with obesity or
intensive care units (NICUs) and the need for treatment of jaun- who are overweight, and its impact on maternal and infant health
dice (yellow pigmentation of infant’s skin or eyes due to a build outcomes is required. To our knowledge, there are no published
up of bilirubin in the blood) and hypoglycaemia (low blood sugar systematic reviews of the use of metformin during pregnancy for
levels) (Cedergren 2004; Dodd 2011; Ehrenberg 2004; Sebire women with obesity or who are overweight.
2001; Weiss 2004; Yu 2006). It has been estimated that the costs
of providing antenatal and postpartum care for women who are
overweight are increased by 23% when compared with women of
normal BMI, increasing further to 37% for women with obesity
(Morgan 2014). OBJECTIVES
There has been considerable interest in providing antenatal dietary
To evaluate the role of metformin in pregnant women with obesity
and lifestyle advice for women with obesity or who are overweight
or who are overweight, on maternal and infant outcomes, includ-
during pregnancy, as a strategy to limit gestational weight gain
ing adverse effects of treatment and costs.
and improve maternal and infant health. However, such antenatal
interventions appear to have a modest effect on gestational weight
gain and other clinical pregnancy and birth outcomes (i-WIP
Collaborative Group 2017), and additional strategies are required. METHODS
Criteria for considering studies for this review 13. Adverse effects associated with treatment, including nausea,
vomiting, diarrhoea
14. Postpartum haemorrhage, as defined by the trial authors
Types of studies 15. Postpartum infectious morbidity
All randomised controlled trials and quasi-randomised trials that 16. Venous thromboembolic event
evaluate metformin use (compared with placebo or no metformin) 17. High-dependency unit admission
in women with obesity or who are overweight in pregnancy for 18. Pregnancy-related maternal death, defined as during
improving outcomes, alone or in combination with other inter- pregnancy or within 42 days of conclusion of pregnancy
ventions were eligible for inclusion. Trials published in abstract 19. Quality of life, as defined by the trial authors
form were eligible for inclusion.
In future updates, trials using a cluster-randomised trials as well
For the infant
as any relevant arms of any multi-armed trials will be eligible for
inclusion. Trials using a cross-over design were not considered for 1. Birthweight (g)
inclusion. 2. Birthweight < 2500 g
3. Birthweight ≥ 4000 g
4. Hypoglycaemia requiring treatment
Types of participants 5. Hyperbilirubinaemia requiring treatment
Pregnant women with obesity or who are overweight, defined as 6. Birth trauma, as defined by the trial authors
women with booking or early pregnancy or pre-pregnancy body 7. Apgar less than 7 at five minutes
mass index (BMI) ≥ 25.0 kg/m2 and excluding women with pre- 8. Neonatal intensive care unit (NICU) admission (including
existing diabetes or polycystic ovarian syndrome. neonatal unit)
9. Perinatal death (i. stillbirth, defined as fetal death ≥ 20
weeks’ gestation and before birth is completed, that is not due to
Types of interventions
an induced termination; ii. neonatal death, defined as death of
Metformin versus placebo or no metformin (alone or in combi- liveborn infant < 28 days old)
nation with other interventions). 10. Breastfeeding at discharge
Types of outcome measures Costs to the health services

1. Antenatal admission to hospital, length of stay
Primary outcomes 2. Length of stay in high-dependency unit or NICU
1. Large-for-gestational-age infant, defined as birthweight ≥
90th percentile for gestational age and infant sex
Search methods for identification of studies
Secondary outcomes The search methods section of this review is based on a standard
template used by Cochrane Pregnancy and Childbirth.
For the woman

1. Gestational weight gain Electronic searches
2. Gestational hypertension We searched Cochrane Pregnancy and Childbirth’s Trials Register
3. Pre-eclampsia by contacting their Information Specialist (11 October 2017).
4. Gestational diabetes, as defined by the trial authors The Register is a database containing over 24,000 reports of con-
5. Preterm birth, defined as birth before 37 weeks trolled trials in the field of pregnancy and childbirth. For full
6. Preterm birth, defined as birth before 34 weeks current search methods used to populate Pregnancy and Child-
7. Preterm premature rupture of membranes, defined as birth’s Trials Register, including the detailed search strategies for
rupture of membranes before 37 completed weeks of pregnancy CENTRAL, MEDLINE, Embase and CINAHL, the list of hand-
8. Induction of labour searched journals and conference proceedings, and the list of jour-
9. Vaginal birth nals reviewed via the current awareness service, please follow this
10. Caesarean birth link to the editorial information about Cochrane Pregnancy and
11. Shoulder dystocia Childbirth in the Cochrane Library and select the ’Specialized
12. Third- or fourth-degree perineal tear Register’ section from the options on the left side of the screen.
Briefly, Cochrane Pregnancy and Childbirth’s Trials Register is Manager 5 software (Review Manager 2014), and checked for ac-
maintained by their Information Specialist and contains trials curacy.
identified from: When information regarding any of the above was unclear, we
1. monthly searches of the Cochrane Central Register of attempted to contact authors of the original reports to provide
Controlled Trials (CENTRAL); further details.
2. weekly searches of MEDLINE (Ovid);
3. weekly searches of Embase (Ovid);
4. monthly searches of CINAHL (EBSCO); Assessment of risk of bias in included studies
5. handsearches of 30 journals and the proceedings of major Two review authors independently assessed risk of bias (AD and
conferences; RG) for each study using the criteria outlined in the Cochrane
6. weekly current awareness alerts for a further 44 journals Handbook for Systematic Reviews of Interventions (Higgins 2011).
plus monthly BioMed Central email alerts. We resolved any disagreement by discussion or by involving a third
Search results are screened by two people and the full text of all review author (JD).
relevant trial reports identified through the searching activities de-
scribed above is reviewed. Based on the intervention described,
(1) Random sequence generation (checking for possible
each trial report is assigned a number that corresponds to a spe-
selection bias)
cific Pregnancy and Childbirth review topic (or topics), and is
then added to the Register. The Information Specialist searches the We described for each included study the method used to generate
Register for each review using this topic number rather than key- the allocation sequence in sufficient detail to allow an assessment
words. This results in a more specific search set that has been fully of whether it should produce comparable groups.
accounted for in the relevant review sections (Included studies; We assessed the method as:
Ongoing studies). • low risk of bias (any truly random process, e.g. random
In addition, we searched ClinicalTrials.gov and the World Health number table; computer random number generator);
Organization ( WHO) International Clinical Trials Registry Plat- • high risk of bias (any non-random process, e.g. odd or even
form ( ICTRP) for unpublished, planned and ongoing trial re- date of birth; hospital or clinic record number);
ports (11 October 2017) (see: Appendix 1 for full search methods • unclear risk of bias.
used).
(2) Allocation concealment (checking for possible selection
Searching other resources bias)
We searched the reference lists of retrieved studies. We did not We described for each included study the method used to con-
apply any language or date restrictions. ceal allocation to interventions prior to assignment and assessed
whether intervention allocation could have been foreseen in ad-
vance of, or during recruitment, or changed after assignment.
Data collection and analysis We assessed the methods as:
• low risk of bias (e.g. telephone or central randomisation;
The methods section of this review is based on a standard template
consecutively numbered sealed opaque envelopes);
used by Cochrane Pregnancy and Childbirth.
• high risk of bias (open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth);
Selection of studies • unclear risk of bias.
Two review authors (AD and RG) independently assessed for in-
clusion all the potential studies we identified as a result of the (3.1) Blinding of participants and personnel (checking for
search strategy. We resolved any disagreement through discussion possible performance bias)
or, if required, we consulted a third review author (JD).
We described for each included study the methods used, if any, to
blind study participants and personnel from knowledge of which
Data extraction and management intervention a participant received. We considered that studies are
We designed a form to extract data (JD). Data extracted also in- at low risk of bias if they were blinded, or if we judged that the
cluded sources of trial funding, trial dates and trial authors’ dec- lack of blinding would be unlikely to affect results. We assessed
larations of interest. For eligible studies, at least two review au- blinding separately for different outcomes or classes of outcomes.
thors extracted the data (AD and RG) using the agreed form. We We assessed the methods as:
resolved discrepancies through discussion or, if required, we con- 1. low, high or unclear risk of bias for participants;
sulted a third review author (JD). We entered data into Review 2. low, high or unclear risk of bias for personnel.
(3.2) Blinding of outcome assessment (checking for possible • We described for each included study any important
detection bias) concerns we had about other possible sources of bias.
We described for each included study the methods used, if any, to
blind outcome assessors from knowledge of which intervention a
participant received. We assessed blinding separately for different (7) Overall risk of bias
outcomes or classes of outcomes.
We assessed methods used to blind outcome assessment as: We made explicit judgements about whether studies are at high risk
• low, high or unclear risk of bias. of bias, according to the criteria given in the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011). With reference
to (1) to (6) above, we assessed the likely magnitude and direction
(4) Incomplete outcome data (checking for possible attrition of the bias and whether we considered it was likely to impact on
bias due to the amount, nature and handling of incomplete the findings. We planned to explore the impact of the level of bias
outcome data) through undertaking sensitivity analyses - see Sensitivity analysis.
We described for each included study, and for each outcome or
class of outcomes, the completeness of data including attrition and
exclusions from the analysis. We stated whether attrition and ex- Assessment of the quality of the evidence using the
clusions were reported and the numbers included in the analysis at GRADE approach
each stage (compared with the total randomised participants), rea-
sons for attrition or exclusion where reported, and whether miss- For this review we assessed the quality of the evidence using the
ing data were balanced across groups or were related to outcomes. GRADE approach, as outlined in the GRADE handbook, in or-
Where sufficient information is reported, or could be supplied by der to assess the quality of the body of evidence relating to the
the trial authors, we planned to reinclude missing data in the anal- following outcomes for the main comparison (metformin versus
yses which we undertake. placebo).
We assessed methods as: 1. Large-for-gestational-age infant, defined as birthweight ≥
• low risk of bias (e.g. no missing outcome data; missing 90th percentile for gestational age and infant sex
outcome data balanced across groups with level of missing data < 2. Gestational diabetes, as defined by trial authors
20%); 3. Birthweight (g)
• high risk of bias (e.g. numbers or reasons for missing data 4. Pre-eclampsia
imbalanced across groups; ‘as treated’ analysis done with 5. Gestational hypertension
substantial departure of intervention received from that assigned 6. Gestational weight gain
at randomisation; level of missing data ≥ 20%); 7. Diarrhoea
• unclear risk of bias. We used GRADEpro Guideline Development Tool to import data
from Review Manager 5 in order to create ’Summary of findings’
tables (Review Manager 2014). We produced a summary of the
(5) Selective reporting (checking for reporting bias) intervention effect and a measure of quality for each of the above
We described for each included study how we investigated the outcomes using the GRADE approach. The GRADE approach
possibility of selective outcome reporting bias and what we found. uses five considerations (study limitations, consistency of effect,
We assessed the methods as: imprecision, indirectness and publication bias) to assess the quality
• low risk of bias (where it is clear that all of the study’s of the body of evidence for each outcome. The evidence can be
prespecified outcomes and all expected outcomes of interest to downgraded from ’high quality’ by one level for serious (or by
the review have been reported); two levels for very serious) limitations, depending on assessments
• high risk of bias (where not all the study’s prespecified for risk of bias, indirectness of evidence, serious inconsistency,
outcomes have been reported; one or more reported primary imprecision of effect estimates or potential publication bias.
outcomes were not prespecified; outcomes of interest are
reported incompletely and so cannot be used; study fails to
include results of a key outcome that would have been expected
Measures of treatment effect
to have been reported);
• unclear risk of bias.
(6) Other bias (checking for bias due to problems not Dichotomous data
covered by (1) to (5) above) For dichotomous data, we presented results as summary risk ratio
(RR) with 95% confidence intervals (CIs).
Continuous data Assessment of heterogeneity
For continuous data, we used the mean difference (MD) if out- We assessed statistical heterogeneity in each meta-analysis using
comes are measured in the same way between trials. We used the the I² and Chi² statistics and Tau2 . We regarded heterogeneity as
standardised mean difference (SMD) to combine trials that mea- substantial if I² is greater than 30% and either Tau2 is greater than
sure the same outcome, but use different methods. zero, or there is a low P value (less than 0.10) in the Chi² test for
heterogeneity.
Unit of analysis issues Assessment of reporting biases

In future updates, if there are 10 or more studies in the meta-
analysis we will investigate reporting biases (such as publication
bias) using funnel plots. We will assess funnel plot asymmetry
Cluster-randomised trials
visually. If asymmetry is suggested by a visual assessment, we will
We did not identify any cluster-randomised controlled trials for in- perform exploratory analyses to investigate it.
clusion in this version of the review. If we identify any for inclusion
in subsequent updates, we will include them in the analyses along
Data synthesis
with individually-randomised trials. We will adjust their sample
sizes using the methods described in the Cochrane Handbook for We carried out statistical analysis using the Review Manager 5
Systematic Reviews of Interventions (Higgins 2011), using an esti- software (Review Manager 2014). We used a fixed-effect meta-
mate of the intracluster correlation coefficient (ICC) derived from analysis for combining data where it was reasonable to assume that
the trial (if possible), from a similar trial or from a study of a sim- studies are estimating the same underlying treatment effect, i.e.
ilar population. If we use ICCs from other sources, we will report where trials are examining the same intervention, and the trials’
this and conduct sensitivity analyses to investigate the effect of populations and methods were judged to be sufficiently similar. If
variation in the ICC. If we identify both cluster-randomised trials there was clinical heterogeneity sufficient to expect that the un-
and individually-randomised trials, we plan to synthesise the rel- derlying treatment effects might differ between trials, or if sub-
evant information. We will consider it reasonable to combine the stantial statistical heterogeneity was detected, we used a random-
results from both if there is little heterogeneity between the study effects meta-analysis to produce an overall summary if an average
designs and the interaction between the effect of intervention and treatment effect across trials was considered clinically meaningful.
the choice of randomisation unit is considered to be unlikely. We then treated the random-effects summary as the average range
We will also acknowledge heterogeneity in the randomisation unit of possible treatment effects and we discussed the clinical impli-
and perform a sensitivity analysis to investigate the effects of the cations of treatment effects differing between trials. If the average
randomisation unit. treatment effect was not clinically meaningful we did not combine
trials.
Where we used random-effects analyses, we presented the results
as the average treatment effect with 95% CIs, and the estimates of
Cross-over trials
Tau² and I².
We did not include cross-over trials in this review.
Subgroup analysis and investigation of heterogeneity
If we had identified substantial heterogeneity, we had planned to
Dealing with missing data
investigate it using subgroup analyses and sensitivity analyses. We
For included studies, we noted levels of attrition. We planned to considered whether an overall summary was meaningful, and if it
explore the impact of including studies with high levels of missing was, used random-effects analysis to produce it.
data in the overall assessment of treatment effect by using sensi- We planned to carry out the following subgroup analyses. The
tivity analysis. currently included studies were similar in BMI inclusion criteria
For all outcomes, we carried out analyses, as far as possible, on and gestational age at enrolment.
an intention-to-treat basis, i.e. we attempted to include all partic- 1. Obesity subclass (BMI 30.0 to 34.9 kg/m2 versus BMI 35.0
ipants randomised to each group in the analyses, and all partici- to 39.9 kg/m2 versus BMI ≥ 40 kg/m2 ).
pants will be analysed in the group to which they were allocated, 2. Time of commencing therapy (trimester 1 versus trimester
regardless of whether or not they received the allocated interven- 2 and later).
tion. The denominator for each outcome in each trial was the The following outcome will be used in subgroup analysis.
number randomised minus any participants whose outcomes are 1. Large-for-gestational age, defined as birthweight > 90
known to be missing. percentile for gestational age and infant sex.
In future updates we plan to assess subgroup differences by in- updates of this review.
teraction tests available within Review Manager (Review Manager
2014). We planned to report the results of subgroup analyses quot-
ing the Chi2 statistic and P value, and the interaction test I² value.
RESULTS
Sensitivity analysis
We planned to carry out sensitivity analysis to explore the effects Description of studies
of trial quality assessed by allocation concealment and other risk of
bias components, by omitting studies rated as high risk of bias for
these components, however there were too few included studies. Results of the search
We will carry out sensitivity analysis to investigate the effect of The search retrieved 37 reports in total (see Figure 1). We screened
randomisation unit in future updates of this review if we identify out 24 reports. Three studies (10 reports) were eligible for inclu-
any cluster-randomised trials. We will restrict sensitivity analysis to sion. Two studies (three reports) are ongoing (see Characteristics
the primary outcome if we can include sufficient studies in future of ongoing studies).
Figure 1. Study flow diagram.
We did not identify any studies reported as abstracts only. We
did not identify any studies of metformin in combination with Interventions and comparisons
another treatment. We did not identify any cluster-randomised All three included studies compared metformin with placebo. Met-
trials. formin was started in the early second trimester in all studies.
Doses ranged from 500 mg twice a day (total 1 g/day) in the
Included studies PACTR201505001142202 trial to 3 g per day in the Syngelaki
2016 trial. The Chiswick 2015 trial utilised a maximum met-
We included three studies involving 1099 randomised partici- formin dose of 2.5 g/day in two to three divided doses, titrated
pants, with outcomes available for 1034 participants (Chiswick from a starting dose of 500 mg/day.
2015; PACTR201505001142202; Syngelaki 2016). Chiswick
2015 enrolled women from February 2011 to January 2014,
Syngelaki 2016 enrolled women from October 2010 to June 2015. Outcomes
The PACTR201505001142202 trial report did not include the Outcome reporting across the three included studies varied. The
dates of enrolment. PACTR201505001142202 trial reported gestational hyperten-
sion, gestational diabetes, and infant birthweight only. The pri-
mary outcome for the Chiswick 2015 trial was birthweight z-score
Design
corresponding to the gestational age, parity, and sex-standardised
All three included studies were reported to be randomised birthweight percentile of liveborn babies delivered at 24 or more
controlled trials (Chiswick 2015; PACTR201505001142202; weeks’ gestation. This trial also reported a range of secondary out-
Syngelaki 2016). comes for women and infants, including biochemical and inflam-
matory markers such as glucose, insulin, and lipids, and measures
of maternal body composition. The Syngelaki 2016 trial utilised
Sample size a similar primary outcome relating to infant birthweight z-score,
The available sample size ranged from 200 in the and also reported a range of secondary clinical outcomes.
PACTR201505001142202 trial to 450 women in the Chiswick
2015 and Syngelaki 2016 trials.
Funding sources
One trial did not report information on funding sources (
Setting PACTR201505001142202). The Chiswick 2015 trial was funded
One trial was conducted in a maternity hospital in Alexandria, by a grant from the Medical Research Council, National Institute
Egypt (PACTR201505001142202). The remaining two studies for Health Research (NIHR) and Tommy’s, the baby charity. The
were conducted in National Health System (NHS) hospitals in funding bodies had no role in any part of the study design, con-
the UK (Chiswick 2015; Syngelaki 2016). duct or data collection and analysis. The Syngelaki 2016 trial was
funded by a grant from the Fetal Medicine Foundation.
Participants
Declarations of interest (reported by the trialists)
The study conducted in Egypt included women with BMI ≥ 35
The authors of the included studies declared having no conflicts
kg/m2 (PACTR201505001142202). Chiswick and colleagues in-
of interest.
cluded pregnant women with BMI ≥ 30.0 kg/m2 , and who were
identified to have a normal glucose tolerance test; exclusion cri-
teria included women who were non-white, who had a previous Excluded studies
history of gestational diabetes, a small baby, or early pre-eclamp- There are no excluded studies in this review.
sia (Chiswick 2015). Syngelaki and colleagues included pregnant
women with BMI (measured at 12 to 18 weeks of pregnancy) ≥
35 kg/m2 (Syngelaki 2016). There were no studies that included
Risk of bias in included studies
women who were overweight, classified as a BMI of 25.0 kg/m2 For a summary of our risk of bias assessments please see Figure 2
to 29.9 kg/m2 . and Figure 3.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
Women who received metformin or placebo had a similar risk of
We assessed the risk of bias as low for allocation concealment in their baby being born with a birthweight considered to be large
two studies (Chiswick 2015; Syngelaki 2016), and unclear risk in for his or her gestational age (> 90th centile for gestational age
one study (PACTR201505001142202). and infant sex) (risk ratio (RR) 0.95, 95% confidence interval
(CI) 0.70 to 1.30; 2 studies, 831 infants, I2 = 0%; high-quality
evidence; Analysis 1.1).
Blinding
We assessed two studies as low risk of bias as they described
their studies as blinded and used an identically appearing placebo Secondary outcomes (maternal)
(Chiswick 2015; Syngelaki 2016), with the Chiswick 2015
study stating “Participants, caregivers, and study personnel were
masked to treatment assignment”. It is unclear if the study by Gestational weight gain
PACTR201505001142202 was blinded. Women who received metformin may have a slightly lower gesta-
tional weight gain compared with women who received placebo
(mean difference (MD) -2.60 kg, 95% CI -5.29 to 0.10 kg; 3
Incomplete outcome data studies, 899 women, random-effects, I2 = 96%, Tau2 = 5.41; low-
We assessed the overall risk of attrition bias as low, with data quality evidence; Analysis 1.2), although there was a high degree
available on 94% of the women enrolled in the three included of heterogeneity between the two included trials.
studies (Chiswick 2015; PACTR201505001142202; Syngelaki
2016).
Gestational hypertension
There may be little or no difference in risk of gestational hyperten-
Selective reporting sion between women who received metformin or placebo (average
We assessed risk of selective reporting bias as low for two studies RR 1.02, 95% CI 0.54 to 1.94; 3 studies, 1040 women, I2 = 38%,
with available trial registrations (Chiswick 2015; Syngelaki 2016). Tau2 = 0.12; low-quality evidence; Analysis 1.3). There was a high
We assessed the PACTR201505001142202 study as having a high degree of heterogeneity between the three included trials.
risk of reporting bias because one of two specified outcomes was
not reported.
Pre-eclampsia
Metformin may make little or no difference in the risk of women
Other potential sources of bias developing pre-eclampsia (average RR 0.74, 95% CI 0.09 to 6.28;
We did not detect any other potential sources of bias in two studies 2 studies, 840 women, random-effects, I2 = 86%, Tau2 = 2.06;
(Chiswick 2015; PACTR201505001142202), and decided it was low-quality evidence; Analysis 1.4), although there was a high
unclear for one study (Syngelaki 2016); this study’s trial registra- degree of heterogeneity between the two included trials.
tion occurred after recruitment commenced.
Gestational diabetes, as defined by the trial authors

Effects of interventions
There is probably little or no difference in the rates of gestational
See: Summary of findings for the main comparison Metformin diabetes between groups of women who received metformin or
compared to placebo for women with obesity during pregnancy placebo (RR 0.85, 95% CI 0.61 to 1.19; 3 studies, 892 women,
Summary of findings for the main comparison. I2 = 16%; moderate-quality evidence; Analysis 1.5).
Metformin versus placebo Preterm birth, defined as birth before 37 weeks

There were no clear differences in the risk of a baby being born
before 37 weeks of pregnancy for women who received metformin
Primary outcomes
compared with women who received placebo (average RR 0.89,
95% CI 0.41 to 1.93; 2 studies, 831 women, random-effects, I2
= 63%, Tau2 = 0.20; Analysis 1.6). We observed a high level of
Large-for-gestational-age infant
heterogeneity.
Preterm birth, defined as birth before 34 weeks Compared to women who received placebo, women in the met-
This outcome was not reported in the included studies. formin group were more likely to experience at least one adverse ef-
fect (RR 1.63, 95% CI 1.27 to 2.08; 1 study, 400 women; Analysis
1.13).
Preterm premature rupture of membranes, defined as rupture
of membranes before 37 completed weeks of pregnancy
The rate of preterm premature rupture of membranes was similar Adverse effects - abdominal pain
for women who received metformin (4/202) and those women
The number of women who reported abdominal pain during the
who received placebo (6/198) (RR 0.65, 95% CI 0.19 to 2.28; 1
studies did not differ between women receiving metformin (63/
study, 400 women; Analysis 1.7).
401) or placebo (56/396) (RR 1.12, 95% CI 0.81 to 1.54; 2
studies, 797 women, I2 = 0%; Analysis 1.14).
Induction of labour
Women who received metformin (78/214) or placebo (96/221)
had similar rates of induction of labour (RR 0.84, 95% CI 0.67 Adverse effects - diarrhoea
to 1.06; 1 study, 435 women; Analysis 1.8). Women receiving metformin were more likely to report experi-
encing diarrhoea (118/401) during study participation compared
with women receiving placebo (50/396) (RR 2.34, 95% CI 1.74
Vaginal birth to 3.14; 2 studies, 797 women, I2 = 0%; high-quality evidence;
The rate of vaginal birth was similar for women who received Analysis 1.15).
metformin (257/416) and women who received placebo (244/
416) (RR 1.06, 95% CI 0.95 to 1.18; 2 studies, 832 women, I2 =
0%; Analysis 1.9).
Adverse effects - headache
The number of women who reported headache during the studies
Caesarean birth was similar for women receiving metformin (86/401) or placebo
The rate of caesarean birth was similar for women who received (76/396) (RR 1.32, 95% CI 0.64 to 2.70; 2 studies, 797 women,
metformin (145/421) and women who received placebo (158/ random-effects, I2 = 72%, Tau2 = 0.020; Analysis 1.16).
417) (RR 0.91, 95% CI 0.76 to 1.08; 2 studies, 838 women, I2 =
0%; Analysis 1.10).
Postpartum haemorrhage, as defined by the trial authors
There were similar rates of postpartum haemorrhage between the
Shoulder dystocia group of women who received metformin (39/414) or placebo
(37/411) (RR 1.05, 95% CI 0.68 to 1.61; 2 studies, 825 women,
The risk of shoulder dystocia was similar for women who received
I2 = 0%; Analysis 1.17).
metformin (2/418) or placebo (4/418) (RR 0.54, 95% CI 0.12 to
2.53; 2 studies, 846 women, I2 = 0%; Analysis 1.11).
Postpartum infectious morbidity
Third- or fourth-degree perineal tear This outcome was not reported in the included studies.
There were similar rates of third- or fourth-degree perineal tear

for women who received metformin (2/202) or placebo (1/195) Venous thromboembolic event
(RR 1.93, 95% CI 0.18 to 21.12; 1 study, 397 women; Analysis This outcome was not reported in the included studies.
1.12).
High-dependency unit admission

Adverse effects associated with treatment, including nausea,
This outcome was not reported in the included studies.
vomiting, diarrhoea
Pregnancy-related maternal death, defined as during

pregnancy or within 42 days of conclusion of pregnancy
Adverse effects (at least one)
Quality of life, as defined by the trial authors Perinatal death
Secondary outcomes (infant) Stillbirth (fetal death ≥ 20 weeks’ gestation and before birth
is completed, that is not due to an induced termination)
The risk of stillbirth was similar between the metformin (3/423)
Birthweight (g)
and placebo (2/420) groups; (RR 1.39, 95% CI 0.28 to 6.97; 2
There was little or no difference in infant birthweight for the studies, 846 babies, I2 = 30%; Analysis 1.24).
babies of women who received metformin or placebo (MD 6.39
g, 95% CI -81.15 to 93.92 g; 2 studies, 834 infants; high-quality
evidence; Analysis 1.18).
Neonatal death (death of liveborn infant < 28 days old)
The risk of an infant dying within their first 28 days (neonatal
Birthweight < 2500 g
death) was similar for babies of women who received metformin
This outcome was not reported in the included studies. (1/416) or placebo (3/418) (RR 0.43, 95% CI 0.06 to 2.91; 2
studies, 834 babies, I2 = 0%; Analysis 1.25).
Birthweight ≥ 4000 g
This outcome was not reported in the included studies. Breastfeeding at discharge
Hypoglycaemia requiring treatment
The rate of neonatal hypoglycaemia was similar for babies of Secondary outcomes (costs to the health services)
women who received metformin (9/202) or placebo (11/195) (RR
0.79, 95% CI 0.33 to 1.86; 1 study, 397 women; Analysis 1.19).
Antenatal admission to hospital, length of stay
Hyperbilirubinaemia requiring treatment This outcome was not reported in the included studies.
The rate of neonatal hyperbilirubinaemia was similar for babies
of women who received metformin (11/202) or placebo (15/195) Length of stay in high-dependency unit or NICU
(RR 0.71, 95% CI 0.33 to 1.50; 1 study, 397 babies; Analysis
1.20).
Birth trauma, as defined by the trial authors

The number of babies with birth trauma was similar for babies of DISCUSSION
women who received metformin or placebo (RR 0.97, 95% CI
0.20 to 4.73; 1 study, 397 babies; Analysis 1.21).
Summary of main results
Apgar less than 7 at five minutes Three studies met our criteria for inclusion in the review; all of
There were a similar number of babies with an Apgar score of less the identified trials contributed data to some of the analyses, these
than 7 at five minutes in the metformin (1/202) and placebo (3/ trials had a combined sample size of 1099 women (with outcome
195) groups (RR 0.32, 95% CI 0.03 to 3.07; 1 study, 397 babies; data available for 1034 participants). All of the included stud-
Analysis 1.22). ies compared oral metformin therapy with placebo in pregnant
women with obesity.
Women who received metformin or placebo had a similar risk of
Neonatal intensive care unit (NICU) admission (including their baby being born large for his or her gestational age. Overall,
neonatal unit) for pregnant women with obesity, the administration of metformin
There were similar numbers of babies admitted to the NICU or appears to be associated with slightly lower gestational weight gain,
neonatal unit in the metformin (11/202) and placebo groups (14/ but an increased risk of experiencing diarrhoea. However, there
195) (RR 0.76, 95% CI 0.35 to 1.63; 1 study, 397 babies; Analysis were no other clear differences identified in the reporting of met-
1.23). formin-related side effects
Overall, there were few clear differences between women receiv- on study design limitations, imprecision, and inconsistency. See
ing metformin and women receiving placebo, reflecting in part, Summary of findings for the main comparison.
the small number of studies contributing data and the resultant
insufficient evidence to identify differences between groups.
Long-term follow-up of maternal and child participants was lack-
Potential biases in the review process
ing in the included trials, and will be necessary to inform any ev-
idence of benefits or harms on outcomes beyond the immediate We acknowledge that there is the potential for bias at all stages of
neonatal period. performing a systematic review. We attempted to minimise bias in
a number of ways; for example, two review authors independently
carried out data extraction and assessed risk of bias.
Overall completeness and applicability of
evidence
The applicability of findings from this systematic review and meta-
Agreements and disagreements with other
studies or reviews
analysis in pregnant women with obesity receiving metformin dur-
ing pregnancy is broadly consistent with the findings reported in As highlighted above, we are aware of no other systematic reviews
the individual included trials. To our knowledge, there have been conducted and reported in the literature on this topic involving
no other systematic reviews conducted and reported in the litera- pregnant women with obesity or who are overweight.
ture on this topic involving pregnant women with obesity or who
are overweight.
The individual trial characteristics highlight the variation in inclu-
sion criteria relating to maternal body mass index (BMI), the dose
of metformin administered and consistency in the definitions of
AUTHORS’ CONCLUSIONS
outcomes reported. Invariably, the available information is limited
by the characteristics of the included studies. The included studies Implications for practice
randomised women with BMI ≥ 30 kg/m2 , the findings therefore Women who received metformin or placebo had a similar risk of
can only be considered for this group of women and not women their baby being born large for his or her gestational age. Overall,
who would be classified as overweight (BMI 24 kg/m2 to 29.9 kg/ for pregnant women with obesity, the administration of metformin
m2 inclusive). appears to be associated with slightly lower gestational weight gain,
The longer-term effects of exposure to metformin during preg- but an increased risk of experiencing diarrhoea.
nancy does not suggest an increased risk of harms (Gilbert 2006;
Hawthorne 2006; Lilja 2006), although the publication of trials Overall, there is insufficient evidence to support the use of met-
included in this review are recent, and outcomes beyond the im- formin for women with obesity during pregnancy to improve ma-
mediate neonatal period are to date unavailable. ternal and infant outcomes. The quality of the evidence in this
review varied from high to low, with downgrading decisions based
on study design limitations, imprecision and inconsistency. There
were only a small number of studies included in this review. Fur-
Quality of the evidence thermore, none of the included studies included women cate-
Overall, we assessed two of the three included studies as be- gorised as ’overweight’ and no trials looked at metformin in com-
ing at low risk of bias overall (Chiswick 2015; Syngelaki 2016), bination with another treatment.
with insufficient information available to reliably assess the third
(PACTR201505001142202). Two of the trials were at low risk Implications for research
of bias with adequate sequence generation and allocation conceal- Future research is required to further evaluate the role of met-
ment, and utilised an adequate placebo, thereby ensuring adequate formin therapy in pregnant women with obesity or who are over-
blinding (Chiswick 2015; Syngelaki 2016). The Syngelaki 2016 weight as a strategy to improve maternal and infant health, alone
study was registered after recruitment of participants had com- or as an adjuvant to dietary and lifestyle advice. Future studies
menced. could also include women who are classified as overweight (BMI
The GRADE quality of evidence for the effect of metformin on 25 kg/m2 to 29.9 kg/m2 ).
risk of large-for-gestational-age infants, and maternal side effects
of the intervention (diarrhoea) was high. We graded the evidence
as moderate for gestational diabetes. In contrast, we graded the
evidence for gestational weight gain, gestational hypertension and
pre-eclampsia as low quality. Downgrading decisions were based ACKNOWLEDGEMENTS
As part of the pre-publication editorial process, this review has
been commented on by four peers (an editor and three referees
who are external to the editorial team) and the Group’s Statistical
Adviser.
The National Institute for Health Research (NIHR) provides in-
frastructure funding to Cochrane Pregnancy and Childbirth. The
views and opinions expressed therein are those of the authors and
do not necessarily reflect those of the NIHR, National Health Se-
vice (NHS) or the Department of Health.
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Number 894. Geneva (Switzerland): WHO, 2000. Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Chiswick 2015
Methods Double-blind placebo controlled RCT, stratification by study site and BMI category,
analysis by intention-to-treat; randomisation utilised a web-based service
15 National Health Service hospitals in the UK enrolled women between February 2011
and January 2014
Participants Inlcusion criteria: pregnant women with BMI ≥ 30 kg/m2 , and normal glucose toler-
ance test
Exclusion criteria: pregnant women who were non-white, had a history of previous
GDM, previous small baby, previous early pre-eclampsia, and a range of other conditions
449 women were randomised with 97% included in the analysis. 223 were randomised
to placebo and 226 to metformin
Interventions Experimental intervention: metformin maximum dose 2.5 g/day versus placebo, 2 to
3 divided doses, titrated from a starting dose of 500 mg per day
Control group: matched placebo tablets
Outcomes Primary outcome

1. Z-score corresponding to the gestational age, parity, and sex-standardised
birthweight percentile of liveborn babies delivered at 24 or more weeks’ gestation
Secondary maternal outcome
1. Insulin resistance at 36 weeks’ gestation
Other outcomes
1. Maternal fasting glucose and insulin and 2 hours glucose at 36 weeks
2. Maternal anthropometry and body composition
3. Baby anthropometry and body composition
4. Maternal inflammatory and metabolic outcomes at 36 weeks, including C-
reactive protein (CRP), cholesterol, HDL, LDL, triglycerides, interleukin (IL)-6,
leptin, serum cortisol, non-esterified fatty acids, and the ratio of plasminogen activator
inhibitor 1 to 2
5. Incidence of low birthweight percentile (< 3rd and < 10th)
6. Incidence of other adverse maternal and neonatal outcomes, including maternal
symptoms
7. Maternal plasma metformin concentration to explore tablet-taking in the
metformin group
8. Maternal metabolic (fasting glucose and insulin and 2-hour glucose) and
inflammatory markers at 28 weeks
Notes The trial was funded by a grant from the Medical Research Council, National Institute
for Health Research (NIHR) and Tommy’s, the baby charity. The funding bodies had
no role in any part of the study design, conduct or data collection and analysis. The
authors declare no conflicts of interest
Risk of bias
Chiswick 2015 (Continued)
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk Computer-generated block randomisation

bias) procedure (block size of 2 to 4)
Allocation concealment (selection bias) Low risk Participants were randomly assigned to
treatment groups via a web-based alloca-
tion system
Blinding of participants and personnel Low risk Participants received metformin or

(performance bias) matched placebo. Participants, caregivers,
All outcomes and study personnel were masked to treat-
ment assignment
Blinding of outcome assessment (detection Low risk Members of the independent Data Moni-
bias) toring Committee had access to unmasked
All outcomes data reports, but had no contact with study
participants
Incomplete outcome data (attrition bias) Low risk 97% of randomised participants’ outcomes
All outcomes available. Data were not available for 3
(1%) women in the control group, and 12
(5%) in the intervention group
Selective reporting (reporting bias) Low risk Published protocol available
Other bias Low risk None identified
PACTR201505001142202
Methods A prospective study (in the trial registration it is stated to be a RCT)

El Shatby Hospital, Alexandria Egypt. Dates of enrolment not reported
Participants 200 participants with BMI ≥ 35 kg/m2 and normal blood glucose, HbA1C and plasma
insulin, in the early second trimester
Interventions Experimental intervention: metformin 500 mg twice a day versus placebo. 100 women
enrolled
Control intervention: placebo. 100 women enrolled
Outcomes 1. Pre-eclampsia
2. GDM
3. Birthweight
Notes Minimal clinical outcomes

No funding sources reported. Authors report no conflicts of interest
More information requested about all criteria for ’Risk of bias’ assessment - 15/03/2018
PACTR201505001142202 (Continued)
Risk of bias
Random sequence generation (selection Unclear risk Participants were divided into two groups.
bias)
Allocation concealment (selection bias) Unclear risk Not stated
Blinding of participants and personnel Unclear risk Participants received “placebo”, although it
(performance bias) was not stated if the placebo had an iden-
All outcomes tical appearance
Blinding of outcome assessment (detection Unclear risk Not stated

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk Outcomes were reported on all women en-
All outcomes rolled in the study.
Selective reporting (reporting bias) High risk 1 of 2 specified outcomes was not reported.
Other bias Low risk None identified
Syngelaki 2016
Methods Double-blind placebo controlled trial

3 National Health Service hospitals in London, UK enrolled women from October 2010
to June 2015
Participants Inclusion criteria: pregnant women with BMI ≥ 35 (at 12 to 18 weeks)

Exclusion criteria: a maternal age of < 18 years; a major fetal defect observed on the scan
performed at 11 to 13 weeks of gestation; a history of GDM; kidney, liver, or heart failure;
a serious medical condition; hyperemesis gravidarum; treatment with metformin at the
time of screening; known sensitivity to metformin; and miscarriage before randomisation
Interventions Experimental intervention: metformin 500 mg tablets up to 3 g/per day. 225 women
enrolled
Control group: matched placebo. 225 women enrolled
Outcomes Primary outcome

1. Birthweight z-score
Secondary outcomes (maternal)
1. Gestational weight gain
2. GDM
3. Pre-eclampsia
4. Pregnancy-induced hypertension
Syngelaki 2016 (Continued)
5. Caesarean section
6. Postpartum haemorrhage, which was defined as blood loss of 1 L or more
Secondary outcomes (fetus or neonate)
1. Death before 24 weeks of gestation
2. Stillbirth at 24 weeks of gestation or later
3. Preterm birth before 37 weeks of gestation
4. Large-for-gestational age (> 90th percentile)
5. Birth trauma (shoulder dystocia, or brachial plexus injury or fracture)
6. Apgar score < 7 at 5 minutes
7. Admission to a level 2 or 3 neonatal unit
8. Hypoglycaemia
9. Hyperbilirubinaemia requiring phototherapy
10. Respiratory distress, which was defined by the need for more than 4 hours of
respiratory support or supplemental oxygen
Notes This trial was supported by a grant from the Fetal Medicine Foundation
The authors report no conflict of interest relevant to this article
Birthweight and gestational weight gain reported as median and interquartile range
(IQR); author emailed on 29/03/2018 for means and SDs (AD). Author responded with
requested information on 29/03/2018
Risk of bias
Random sequence generation (selection Low risk Computer-generated random numbers

bias)
Allocation concealment (selection bias) Low risk Participants were randomly assigned to
treatment groups via a web-based alloca-
tion system
Blinding of participants and personnel Low risk Participants received metformin or placebo
(performance bias) identical in taste and appearance. States
All outcomes study is double-blind
Blinding of outcome assessment (detection Low risk The Consultant and his healthcare team
bias) would record the clinical data of the partici-
All outcomes pants at each antenatal visit. Delivery notes
and neonatal outcomes for each participant
would be recorded by the healthcare team
Incomplete outcome data (attrition bias) Low risk 23 (10%) of women in the metformin
All outcomes group and 27 (12%) withdrew consent af-
ter randomisation
Selective reporting (reporting bias) Low risk Stated outcomes have been reported.
Syngelaki 2016 (Continued)
Other bias Unclear risk Trial registration occurred after commenc-

ing enrolment of participants
BMI: body mass index

GDM: gestational diabetes mellitus
HDL: high-density lipoprotein
LDL: low-density lipoprotein
RCT: randomised controlled trial
Characteristics of ongoing studies [ordered by study ID]
Dodd 2016
Trial name or title Metformin and dietary advice to improve insulin sensitivity and promote gestational restriction of weight
among pregnant women who are overweight or obese: the GRoW Randomised Trial
Methods Randomised controlled trial across 3 metropolitan hospitals in Adelaide, South Australia. Women were
enrolled from 2013 until 2016
Participants Included: women with BMI ≥ 25 kg/m2 , singleton pregnancy, between 10 + 0 and 20 weeks of gestation,
without type 1, 2 or gestational diabetes
Excluded: women with a contraindication to taking metformin, congenital fetal anomaly or planning to birth
at a hospital not involved with the study
Interventions Intervention: women receive up to 2 g of metformin (titrated from 500 mg over 2 weeks) in divided doses
morning and night, from trial entry until birth
Control: women receive up to 4 tablets daily, identical in taste and appearance to the metformin tablets,
(titrated from 1 tablet over 4 weeks), from trial entry until birth
All women received a comprehensive dietary and lifestyle intervention across the duration of pregnancy
Outcomes 1. Incidence of infants born with birthweight of 4 kg or more

Maternal clinical outcomes
1. Gestational weight gain
2. Birth by caesarean
3. Infection
4. Antenatal admission and length of stay
5. Perineal trauma
6. Shoulder dystocia
7. Postpartum haemorrhage
Infant clinical outcomes
1. Birthweight of 4.5 kg or more
2. Large-for-gestational age
3. Small-for-gestational age
4. Admission to the nursery
5. Hypoglycaemia
6. Hyperbilirubinaemia
Dodd 2016 (Continued)
7. Gestational age at birth

8. Preterm birth
9. Preterm prelabour rupture of the membranes
10. Apgar score of less than 7 at 5 minutes
11. Breastfeeding on hospital discharge
Starting date May 2013
Contact information Jodie Dodd (jodie.dodd@adelaide.edu.au)
Notes
RBR-9rpqdn
Trial name or title Use of metformin for the prevention of gestational diabetes mellitus in obese pregnant women
Methods Randomised controlled trial, Joinville, Brazil
Participants Included: women aged 18 years or more with BMI ≥ 30 kg/m2 , singleton pregnancy, between 10 + 0 and
20 weeks of gestation, without gestational diabetes (screened in early pregnancy); or pathology that interferes
with glucose metabolism
Excluded: women with a contraindication to taking metformin; history or presence of liver disease; gastroin-
testinal disease or other conditions that interfere with the absorption, distribution, excretion or metabolism
of the drug
Interventions Intervention: women will receive 500 mg metformin orally after breakfast and dinner from 20 weeks of
pregnancy until birth; in addition standard monitoring with nutritionist, nurses physiotherapists and obste-
tricians
Control: women will receive standard monitoring with nutritionist, nurses physiotherapists and obstetricians
from 20 weeks of pregnancy until birth
Outcomes Primary outcome: incidence of gestational diabetes

Secondary outcome: neonatal hypoglycaemia
Starting date October 2014
Contact information William Barbosa Sales; Universidade da Região de Joinville. Phone +55 (41) 8859 9064; email: salles-
bio@hotmail.com
Notes
BMI: body mass index
DATA AND ANALYSES
Comparison 1. Metformin versus placebo
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Large-for-gestational-age infant, 2 831 Risk Ratio (M-H, Fixed, 95% CI) 0.95 [0.70, 1.30]
defined as birthweight ≥ 90th
percentile for gestational age
and infant sex
2 Gestational weight gain (kg) 3 899 Mean Difference (IV, Random, 95% CI) -2.60 [-5.29, 0.10]
3 Gestational hypertension 3 1040 Risk Ratio (M-H, Random, 95% CI) 1.02 [0.54, 1.94]
4 Pre-eclampsia 2 840 Risk Ratio (M-H, Random, 95% CI) 0.74 [0.09, 6.28]
5 Gestational diabetes 3 892 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.61, 1.19]
6 Preterm birth (before 37 weeks) 2 831 Risk Ratio (M-H, Random, 95% CI) 0.89 [0.41, 1.93]
7 Preterm premature rupture of 1 400 Risk Ratio (M-H, Fixed, 95% CI) 0.65 [0.19, 2.28]
membranes
8 Induction of labour 1 435 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.67, 1.06]
9 Vaginal birth 2 832 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.95, 1.18]
10 Caesarean birth 2 838 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.76, 1.08]
11 Shoulder dystocia 2 846 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.12, 2.53]
12 Third- or fourth-degree 1 397 Risk Ratio (M-H, Fixed, 95% CI) 1.93 [0.18, 21.12]
perineal tear
13 Adverse effects of the treatment: 1 400 Risk Ratio (M-H, Fixed, 95% CI) 1.63 [1.27, 2.08]
at least one
abdominal pain
diarrhoea
16 Adverse effects of the treatment: 2 797 Risk Ratio (M-H, Random, 95% CI) 1.32 [0.64, 2.70]
headache
17 Postpartum haemorrhage 2 825 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.68, 1.61]
18 Birthweight (g) 2 834 Mean Difference (IV, Fixed, 95% CI) 6.39 [-81.15, 93.92]
19 Hypoglycaemia requiring 1 397 Risk Ratio (M-H, Fixed, 95% CI) 0.79 [0.33, 1.86]
treatment
20 Hyperbilirubinaemia requiring 1 397 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.33, 1.50]
treatment
21 Birth trauma 1 397 Risk Ratio (M-H, Fixed, 95% CI) 0.97 [0.20, 4.73]
22 Apgar less than 7 at five minutes 1 397 Risk Ratio (M-H, Fixed, 95% CI) 0.32 [0.03, 3.07]
23 NICU/Neonatal unit 1 397 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.35, 1.63]
admission
24 Stillbirth 2 843 Risk Ratio (M-H, Fixed, 95% CI) 1.39 [0.28, 6.97]
25 Neonatal death 2 834 Risk Ratio (M-H, Fixed, 95% CI) 0.43 [0.06, 2.91]
Analysis 1.1. Comparison 1 Metformin versus placebo, Outcome 1 Large-for-gestational-age infant, defined
as birthweight ≥ 90th percentile for gestational age and infant sex.
Review: Metformin for women who are overweight or obese during pregnancy for improving maternal and infant outcomes
Comparison: 1 Metformin versus placebo
Outcome: 1 Large-for-gestational-age infant, defined as birthweight ≥ 90th percentile for gestational age and infant sex
Study or subgroup Metformin Placebo Risk Ratio Weight Risk Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Chiswick 2015 31/214 38/220 55.1 % 0.84 [ 0.54, 1.30 ]
Syngelaki 2016 34/202 30/195 44.9 % 1.09 [ 0.70, 1.72 ]
Total (95% CI) 416 415 100.0 % 0.95 [ 0.70, 1.30 ]

Total events: 65 (Metformin), 68 (Placebo)
Heterogeneity: Chi2 = 0.69, df = 1 (P = 0.41); I2 =0.0%
Test for overall effect: Z = 0.30 (P = 0.76)
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours metformin Favours placebo
Analysis 1.2. Comparison 1 Metformin versus placebo, Outcome 2 Gestational weight gain (kg).
Outcome: 2 Gestational weight gain (kg)
Mean Mean
Study or subgroup Metformin Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI
Chiswick 2015 143 6.7 (6) 156 7.23 (4.9) 32.6 % -0.53 [ -1.78, 0.72 ]
PACTR201505001142202 100 6.55 (2.6) 100 11.61 (2.9) 34.0 % -5.06 [ -5.82, -4.30 ]
Syngelaki 2016 202 4.3 (5.1) 198 6.4 (5.1) 33.4 % -2.10 [ -3.10, -1.10 ]
Total (95% CI) 445 454 100.0 % -2.60 [ -5.29, 0.10 ]

Heterogeneity: Tau2 = 5.41; Chi2 = 44.87, df = 2 (P<0.00001); I2 =96%
-20 -10 0 10 20
Favours Metformin Favours Placebo
Analysis 1.3. Comparison 1 Metformin versus placebo, Outcome 3 Gestational hypertension.
Outcome: 3 Gestational hypertension

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Chiswick 2015 21/221 14/222 45.9 % 1.51 [ 0.79, 2.89 ]
PACTR201505001142202 2/100 6/100 13.9 % 0.33 [ 0.07, 1.61 ]
Syngelaki 2016 13/202 13/195 40.1 % 0.97 [ 0.46, 2.03 ]
Total (95% CI) 523 517 100.0 % 1.02 [ 0.54, 1.94 ]

Heterogeneity: Tau2 = 0.12; Chi2 = 3.23, df = 2 (P = 0.20); I2 =38%
0.01 0.1 1 10 100

Analysis 1.4. Comparison 1 Metformin versus placebo, Outcome 4 Pre-eclampsia.
Outcome: 4 Pre-eclampsia

M- M-
n/N n/N CI CI
Chiswick 2015 7/221 3/222 47.2 % 2.34 [ 0.61, 8.95 ]
Syngelaki 2016 6/202 22/195 52.8 % 0.26 [ 0.11, 0.64 ]
Total (95% CI) 423 417 100.0 % 0.74 [ 0.09, 6.28 ]

0.01 0.1 1 10 100

Analysis 1.5. Comparison 1 Metformin versus placebo, Outcome 5 Gestational diabetes.
Outcome: 5 Gestational diabetes

Chiswick 2015 26/142 36/153 55.0 % 0.78 [ 0.50, 1.22 ]
PACTR201505001142202 2/100 6/100 9.5 % 0.33 [ 0.07, 1.61 ]
Syngelaki 2016 25/202 22/195 35.5 % 1.10 [ 0.64, 1.88 ]
Total (95% CI) 444 448 100.0 % 0.85 [ 0.61, 1.19 ]

Heterogeneity: Chi2 = 2.37, df = 2 (P = 0.31); I2 =16%
0.01 0.1 1 10 100

Analysis 1.6. Comparison 1 Metformin versus placebo, Outcome 6 Preterm birth (before 37 weeks).
Outcome: 6 Preterm birth (before 37 weeks)

M- M-
n/N n/N CI CI
Chiswick 2015 18/214 14/220 49.7 % 1.32 [ 0.67, 2.59 ]
Syngelaki 2016 13/202 21/195 50.3 % 0.60 [ 0.31, 1.16 ]
Total (95% CI) 416 415 100.0 % 0.89 [ 0.41, 1.93 ]

0.01 0.1 1 10 100

Analysis 1.7. Comparison 1 Metformin versus placebo, Outcome 7 Preterm premature rupture of
membranes.
Outcome: 7 Preterm premature rupture of membranes

Syngelaki 2016 4/202 6/198 100.0 % 0.65 [ 0.19, 2.28 ]
Total (95% CI) 202 198 100.0 % 0.65 [ 0.19, 2.28 ]

Heterogeneity: not applicable
0.01 0.1 1 10 100

Analysis 1.8. Comparison 1 Metformin versus placebo, Outcome 8 Induction of labour.
Outcome: 8 Induction of labour

Chiswick 2015 (1) 78/214 96/221 100.0 % 0.84 [ 0.67, 1.06 ]
Total (95% CI) 214 221 100.0 % 0.84 [ 0.67, 1.06 ]

0.01 0.1 1 10 100

(1) Chiswick 2015 includes live births only
Analysis 1.9. Comparison 1 Metformin versus placebo, Outcome 9 Vaginal birth.
Outcome: 9 Vaginal birth

Chiswick 2015 (1) 148/214 142/221 57.4 % 1.08 [ 0.94, 1.23 ]
Syngelaki 2016 109/202 102/195 42.6 % 1.03 [ 0.86, 1.24 ]
Total (95% CI) 416 416 100.0 % 1.06 [ 0.95, 1.18 ]

0.01 0.1 1 10 100

(1) Chiswick 2015 includes live births only.
Analysis 1.10. Comparison 1 Metformin versus placebo, Outcome 10 Caesarean birth.
Outcome: 10 Caesarean birth

Chiswick 2015 65/219 76/222 47.5 % 0.87 [ 0.66, 1.14 ]
Syngelaki 2016 80/202 82/195 52.5 % 0.94 [ 0.74, 1.19 ]
Total (95% CI) 421 417 100.0 % 0.91 [ 0.76, 1.08 ]

0.01 0.1 1 10 100

Analysis 1.11. Comparison 1 Metformin versus placebo, Outcome 11 Shoulder dystocia.
Outcome: 11 Shoulder dystocia

Chiswick 2015 0/226 2/223 55.3 % 0.20 [ 0.01, 4.09 ]
Syngelaki 2016 2/202 2/195 44.7 % 0.97 [ 0.14, 6.79 ]
Total (95% CI) 428 418 100.0 % 0.54 [ 0.12, 2.53 ]

0.01 0.1 1 10 100

Analysis 1.12. Comparison 1 Metformin versus placebo, Outcome 12 Third- or fourth-degree perineal tear.
Outcome: 12 Third- or fourth-degree perineal tear

Syngelaki 2016 2/202 1/195 100.0 % 1.93 [ 0.18, 21.12 ]
Total (95% CI) 202 195 100.0 % 1.93 [ 0.18, 21.12 ]

0.01 0.1 1 10 100

Favours Metformin Favours placebo
Analysis 1.13. Comparison 1 Metformin versus placebo, Outcome 13 Adverse effects of the treatment: at
least one.
Outcome: 13 Adverse effects of the treatment: at least one

Syngelaki 2016 103/202 62/198 100.0 % 1.63 [ 1.27, 2.08 ]
Total (95% CI) 202 198 100.0 % 1.63 [ 1.27, 2.08 ]

0.01 0.1 1 10 100

Analysis 1.14. Comparison 1 Metformin versus placebo, Outcome 14 Adverse effects of the treatment:
abdominal pain.
Outcome: 14 Adverse effects of the treatment: abdominal pain

Chiswick 2015 49/199 42/198 74.9 % 1.16 [ 0.81, 1.67 ]
Syngelaki 2016 14/202 14/198 25.1 % 0.98 [ 0.48, 2.00 ]
Total (95% CI) 401 396 100.0 % 1.12 [ 0.81, 1.54 ]

0.01 0.1 1 10 100

diarrhoea.
Outcome: 15 Adverse effects of the treatment: diarrhoea

Chiswick 2015 83/199 37/198 73.9 % 2.23 [ 1.60, 3.12 ]
Syngelaki 2016 35/202 13/198 26.1 % 2.64 [ 1.44, 4.84 ]
Total (95% CI) 401 396 100.0 % 2.34 [ 1.74, 3.14 ]

Test for overall effect: Z = 5.67 (P < 0.00001)
0.01 0.1 1 10 100

headache.
Outcome: 16 Adverse effects of the treatment: headache

M- M-
n/N n/N CI CI
Chiswick 2015 65/199 66/198 60.4 % 0.98 [ 0.74, 1.30 ]
Syngelaki 2016 21/202 10/198 39.6 % 2.06 [ 0.99, 4.26 ]
Total (95% CI) 401 396 100.0 % 1.32 [ 0.64, 2.70 ]

0.01 0.1 1 10 100

Analysis 1.17. Comparison 1 Metformin versus placebo, Outcome 17 Postpartum haemorrhage.
Outcome: 17 Postpartum haemorrhage
Study or subgroup Experimental Control Risk Ratio Weight Risk Ratio

Chiswick 2015 20/212 21/216 56.1 % 0.97 [ 0.54, 1.74 ]
Syngelaki 2016 19/202 16/195 43.9 % 1.15 [ 0.61, 2.16 ]
Total (95% CI) 414 411 100.0 % 1.05 [ 0.68, 1.61 ]

Total events: 39 (Experimental), 37 (Control)
0.01 0.1 1 10 100

Analysis 1.18. Comparison 1 Metformin versus placebo, Outcome 18 Birthweight (g).
Outcome: 18 Birthweight (g)
Mean Mean
Study or subgroup Favours metformin Placebo Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
Chiswick 2015 214 3462 (548) 220 3463 (660) 59.0 % -1.00 [ -115.00, 113.00 ]
Syngelaki 2016 202 3358 (655) 198 3341 (736) 41.0 % 17.00 [ -119.63, 153.63 ]
Total (95% CI) 416 418 100.0 % 6.39 [ -81.15, 93.92 ]

-1000 -500 0 500 1000

Analysis 1.19. Comparison 1 Metformin versus placebo, Outcome 19 Hypoglycaemia requiring treatment.
Outcome: 19 Hypoglycaemia requiring treatment

Syngelaki 2016 9/202 11/195 100.0 % 0.79 [ 0.33, 1.86 ]
Total (95% CI) 202 195 100.0 % 0.79 [ 0.33, 1.86 ]

0.01 0.1 1 10 100

Analysis 1.20. Comparison 1 Metformin versus placebo, Outcome 20 Hyperbilirubinaemia requiring
treatment.
Outcome: 20 Hyperbilirubinaemia requiring treatment

Syngelaki 2016 11/202 15/195 100.0 % 0.71 [ 0.33, 1.50 ]
Total (95% CI) 202 195 100.0 % 0.71 [ 0.33, 1.50 ]

0.01 0.1 1 10 100

Analysis 1.21. Comparison 1 Metformin versus placebo, Outcome 21 Birth trauma.
Outcome: 21 Birth trauma

Syngelaki 2016 3/202 3/195 100.0 % 0.97 [ 0.20, 4.73 ]
Total (95% CI) 202 195 100.0 % 0.97 [ 0.20, 4.73 ]

0.01 0.1 1 10 100

Analysis 1.22. Comparison 1 Metformin versus placebo, Outcome 22 Apgar less than 7 at five minutes.
Outcome: 22 Apgar less than 7 at five minutes

Syngelaki 2016 1/202 3/195 100.0 % 0.32 [ 0.03, 3.07 ]
Total (95% CI) 202 195 100.0 % 0.32 [ 0.03, 3.07 ]

0.01 0.1 1 10 100

Analysis 1.23. Comparison 1 Metformin versus placebo, Outcome 23 NICU/Neonatal unit admission.
Outcome: 23 NICU/Neonatal unit admission

Syngelaki 2016 11/202 14/195 100.0 % 0.76 [ 0.35, 1.63 ]
Total (95% CI) 202 195 100.0 % 0.76 [ 0.35, 1.63 ]

0.01 0.1 1 10 100

Analysis 1.24. Comparison 1 Metformin versus placebo, Outcome 24 Stillbirth.
Outcome: 24 Stillbirth

Chiswick 2015 2/221 0/222 19.8 % 5.02 [ 0.24, 104.02 ]
Syngelaki 2016 1/202 2/198 80.2 % 0.49 [ 0.04, 5.36 ]
Total (95% CI) 423 420 100.0 % 1.39 [ 0.28, 6.97 ]

Heterogeneity: Chi2 = 1.42, df = 1 (P = 0.23); I2 =30%
0.01 0.1 1 10 100

Analysis 1.25. Comparison 1 Metformin versus placebo, Outcome 25 Neonatal death.
Outcome: 25 Neonatal death

Chiswick 2015 1/214 2/220 56.6 % 0.51 [ 0.05, 5.63 ]
Syngelaki 2016 0/202 1/198 43.4 % 0.33 [ 0.01, 7.97 ]
Total (95% CI) 416 418 100.0 % 0.43 [ 0.06, 2.91 ]

0.01 0.1 1 10 100

APPENDICES
Appendix 1. Search methods for ICTRP and ClinicalTrials.gov
ICTRP
Each line was run separately
metformin AND pregnancy AND obes*
metformin AND pregnancy AND overweight
metformin AND pregnancy AND weight
ClinicalTrials.gov
Advanced search, Intervention studies
Intervention = metformin
Condition = obesity, overweight
Other terms = pregnancy
CONTRIBUTIONS OF AUTHORS
Jodie Dodd provided general and methodological advice on the protocol, designed the data extraction template, was consulted over
discrepancies with study selection and data extraction, completed the GRADE assessment, and was involved with data analysis and
interpretation.
Rosalie Grivell provided advice on clinical and methodological aspects of the protocol, screened studies for inclusion, extracted data
and contributed to data analysis and interpretation.
Andrea Deussen provided general advice on the protocol, screened studies for inclusion, extracted data, wrote up the review, completed
the GRADE assessment and contributed to data analysis.
William Hague provided general advice on the protocol and interpreted results.
DECLARATIONS OF INTEREST
Jodie Dodd is chief investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy for women with obesity
or who are overweight (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is
complete. Decisions relating to this trial will be made by third parties not directly involved in the trial.
Rosalie Grivell is an investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy for women with obesity
complete. Decisions relating to this trial will be made by third parties not directly involved in the trial.
William Hague is an investigator of an ongoing randomised trial evaluating the role of metformin in pregnancy women with obesity
complete. Decisions relating to this trial will be made by third parties not directly involved in the trial. He has received NHMRD
MRFF (rare disease) funding for an RCT comparing UDCA with rifampicin in severe early onset Intrahepatic Cholestasis of Pregnancy
(Hague et al 2018-2022) and is an investigator on the MAGDA study on the follow-up of women with previous GDM, funded by a
Partnership grant from NHMRC.
Andrea Deussen is the trial coordinator of a study of a randomised trial evaluating the role of metformin in pregnancy for women
who are obese (Dodd 2016). This trial is potentially eligible for inclusion in future updates of this review when the trial is complete.
Decisions relating to this trial will be made by third parties not directly involved in the trial.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW
There are some differences between the published protocol (Eames 2013), and this full review. These are explained below.
We have changed the title and scope of the review to include women who are overweight (body mass index (BMI) ≥ 25 kg/m2 ).
Jodie Dodd has taken over the role of contact person and guarantor for this review.
We have updated the Background sections.
Our search methods now include the World Health Organization ( WHO) International Clinical Trials Registry Platform ( ICTRP),
and ClinicalTrials.gov, as required by Cochrane standards.
The review now includes women who are overweight (BMI ≥ 25 kg/m2 ). We have added the classification for overweight. We have
amended the Background, Objectives, and Methods, including types of participants, to include women who are overweight.
For clarity, we have changed one secondary outcome from ’admission to high-dependency unit or NICU and length of stay’ to ’Length
of stay in high-dependency unit or NICU’.
We have prepared the review to current Cochrane MECIR standards and the standard methods of Cochrane Pregnancy and Childbirth,
including the use of GRADE and inclusion of Summary of findings for the main comparison.

Dodd 2018

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Cochrane Database of Systematic Reviews

Metformin for women who are overweight or obese during

Dodd JM, Grivell RM, Deussen AR, Hague WM

Dodd JM, Grivell RM, Deussen AR, Hague WM.

Metformin for women who are overweight or obese during

Jodie M Dodd1 , Rosalie M Grivell2 , Andrea R Deussen1 , William M Hague3

Editorial group: Cochrane Pregnancy and Childbirth Group.

PLAIN LANGUAGE SUMMARY

M etformin compared to placebo for women with obesity during pregnancy

Patient or population: wom en with obesity during pregnancy

Risk with placebo Risk with metformin

Large- for- Study population RR 0.95 831 ⊕⊕⊕⊕

Gestational weight The m ean gestational M D 2.60 kilogram s - 899 ⊕⊕

Gestational hyperten- Study population Average RR 1.02 1040 ⊕⊕

Pre- eclampsia Study population Average RR 0.74 840 ⊕⊕

Gestational diabetes Study population RR 0.85 892 ⊕⊕⊕

Adverse effects asso- Study population RR 2.34 797 ⊕⊕⊕⊕

GRADE Working Group grades of evidence

Types of outcome measures Costs to the health services

For the woman

Unit of analysis issues Assessment of reporting biases

Gestational diabetes, as defined by the trial authors

Metformin versus placebo Preterm birth, defined as birth before 37 weeks

There were similar rates of third- or fourth-degree perineal tear

High-dependency unit admission

Pregnancy-related maternal death, defined as during

Birth trauma, as defined by the trial authors

Cedergren 2004 Inzucchi 1998

Characteristics of included studies [ordered by study ID]

Outcomes Primary outcome

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated block randomisation

Blinding of participants and personnel Low risk Participants received metformin or

Selective reporting (reporting bias) Low risk Published protocol available

Other bias Low risk None identified

Methods A prospective study (in the trial registration it is stated to be a RCT)

Notes Minimal clinical outcomes

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk Not stated

Blinding of outcome assessment (detection Unclear risk Not stated

Other bias Low risk None identified

Methods Double-blind placebo controlled trial

Participants Inclusion criteria: pregnant women with BMI ≥ 35 (at 12 to 18 weeks)

Outcomes Primary outcome

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated random numbers

Other bias Unclear risk Trial registration occurred after commenc-

BMI: body mass index

Characteristics of ongoing studies [ordered by study ID]

Outcomes 1. Incidence of infants born with birthweight of 4 kg or more

7. Gestational age at birth

Starting date May 2013

Contact information Jodie Dodd (jodie.dodd@adelaide.edu.au)

Methods Randomised controlled trial, Joinville, Brazil

Outcomes Primary outcome: incidence of gestational diabetes

Starting date October 2014

BMI: body mass index

Comparison 1. Metformin versus placebo

Comparison: 1 Metformin versus placebo

Study or subgroup Metformin Placebo Risk Ratio Weight Risk Ratio

Syngelaki 2016 34/202 30/195 44.9 % 1.09 [ 0.70, 1.72 ]

Total (95% CI) 416 415 100.0 % 0.95 [ 0.70, 1.30 ]

0.01 0.1 1 10 100

Comparison: 1 Metformin versus placebo